Expression of RALT, a feedback inhibitor of ErbB receptors, is subjected to an integrated transcriptional and post-translational control

被引:66
作者
Fiorini, M
Ballarò, C
Sala, G
Falcone, G
Alemà, S
Segatto, O [1 ]
机构
[1] Ist Regina Elena, Immunol Lab, I-00156 Rome, Italy
[2] CNR, Ist Biol Cellulare, I-00016 Monterotondo, Italy
关键词
ErbB; RALT; proteasome; cell cycle; Ras pathways;
D O I
10.1038/sj.onc.1205823
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Over-expression studies have demonstrated that RALT (receptor associated late transducer) is a feedback inhibitor of ErbB-2 mitogenic and transforming signals. In growth-arrested cells, expression of endogenous RALT is induced by mitogenic stimuli, is high throughout mid to late G1 and returns to baseline as cells move into S phase. Here, we show that physiological levels of RALT effectively suppress ErbB-2 mitogenic signals. We also investigate the regulatory mechanisms that preside to the control of RALT expression. We demonstrate that pharmacological ablation of extracellular signal-regulated kinase (ERK) activation leads to blockade of RALT expression, unlike genetic and/or pharmacological interference with the activities of PKC, Src family kinases, p38 SAPK and PI-3K. Tamoxifen-dependent activation of an inducible Raf:ER chimera was sufficient to induce RALT expression. Thus, activation of the Ras-Raf-ERK pathway is necessary and sufficient to drive RALT expression. The RALT protein is labile and was found to accumulate robustly upon pharmacological inhibition of the proteasome. We were able to detect ubiquitin-conjugated RALT species in living cells, suggesting that ubiquitinylation targets RALT for proteasome-dependent degradation. Such an integrated transcriptional and posttranslational control is likely to provide RALT with the ability to fluctuate timely in order to tune ErbB signals.
引用
收藏
页码:6530 / 6539
页数:10
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